Despite advances in genomics in recent years, schizophrenia remains one of the most complex challenges of both genetics and neuroscience. The chromosomal abnormality 22q11 deletion syndrome, also known as DiGeorge syndrome, offers a way in, since it is one of the strongest genetic risk factors for schizophrenia.
Out of dozens of genes within the 22q11 deletion, several encode proteins found in mitochondria. A team of Emory scientists, led by cell biologist Victor Faundez, recently analyzed Read more

cell biology

Earlier today, weÂ posted a notice on Eurekalert for a Sunday, December 13 presentation by graduate student Jessica Konen at theÂ American Society for Cell Biology meeting in San Diego.

Her research, performed with Adam Marcus at Winship Cancer Institute, was the topic of a video that recently won first prize in a contest sponsored by the Association of American Medical Colleges. ThisÂ was our video team’s first use of theÂ “fast hand on whiteboard” effect, and a lot of fun to make. The video’s strength growsÂ out of the footageÂ Konen and Marcus have of cancer cells migrating in culture. Check it out, if you haven’t already.

PosterÂ presentations at the 2015 ASCB meeting can be found by searching this PDF. A few Emory-centric highlights:

This monthâ€™s intriguing image is a set of videos produced by cell biologist James Zhengâ€™s laboratory. Looking at this video of a cell can be mesmerizing. The edges of the cell appear to be flowing inward, like a waterfall. Zheng explains that this is a phenomenon called â€œactin retrograde flow.â€

Actin is a very abundant protein found in animals, plants and fungi that forms filaments, making up the cellâ€™s internal skeleton. What we are seeing with retrograde flow is that molecules of actin are being added to one end of the filaments while coming loose from the other end.

Zhengâ€™s laboratory is studying a protein called cofilin, which disassembles actin filaments. Using a technique called CALI (chromophore-assisted laser inactivation) the scientists http://www.troakley.com/ used a laser to blast cofilin, inactivating it. This is why, partway through the loop, after the word CALI appears, the flow slows down. Postdoctoral fellow Eric Vitriol is the lead author on a paper in Molecular Biology of the Cell that includes these videos.

Anyone studying neuroscience will notice that many neurodegenerative diseases seem to have their own sticky, possibly toxic protein.Â This protein tends to aggregate, or clump together, in or near the cells affected by the disease.

Picture a glass of milk left in a warm place for several days. Yuck. That is the macro version of the microscopic clumps scientists believe are bothering the brain.Â For many diseases, there is a debate: are the clumps by themselves toxic to neurons, or a byproduct of something else killing the cells?

One of them, TDP-43, is found in protein aggregates in most forms of ALS, both familial and sporadic. Mutations in the TDP-43 gene also account for a small fraction of both familial and sporadic forms of ALS. This suggests that even the normal protein can create problems, but a mutated version can accelerate the disease. In addition, TDP-43 aggregates have been connected with other diseases such as frontotemporal dementia.

Again, it’s not clear whether the aggregates themselves are toxic, or whether it’s more a matter of TDP-43, which appears to regulate RNA processing, is not doing what it’s supposed to in the cell.

TDP-43 protein is mobile within motor neurons.

Emory cell biologists Claudia Fallini and Wilfried Rossoll have been probing the effects of tweaking TDP-43 levels in motor neurons, the cell type vulnerable to degeneration in ALS. They find that motor neurons may be more sensitive to changes in TDP-43 levels than other neurons, which may explain why ALS selectively affects motor neurons.

Fallini was able to obtain aÂ movieÂ of fluorescently-tagged TDP-43 “granules” moving around in live motor neurons. Importantly: this is healthy/functional, not aggregated/ toxic protein. The finding that TDP-43 is mobile implies that it has something to do with transporting RNAs around the cell, rather than only functioning in the nucleus.

“Our data pointÂ to the hypothesis that TDP-43 increased localization in theÂ cytoplasm is the early trigger of toxicity, followed by proteinÂ aggregation,” Fallini says. “Because motor neurons are unique neurons due to their highÂ degree of polarization, we believe they might be more sensitive toÂ alterations in TDP-43 functions in the cytoplasm or the axon.”

In particular, the researchers found that elevated levels of TDP-43 provoke motor neurons to shut down axon outgrowth. They focused on a role for the C-terminal end of TDP-43 in this effect.

â€œNobody had looked at TDP-43 specifically in motor neurons before,â€ she says. â€œOur paper for the first time shows the localization and axonal transport of TDP-43, and the effects of TDP-43 altered levels on motor neuron morphology.â€

*Another ALS protein, SOD1 (superoxide dismutase), apparently forms toxic aggregates when mutated in some cases of familial ALS. At Emory, Terrell Brotherton and Jonathan Glass have been investigating these forms of SOD. The third protein, FUS, has similar properties to TDP-43.

The fragile X protein — missing in the most common inherited form of intellectual disability — plays a central role in neurons and how they respond to external signals.Â Cell biologist Gary Bassell and his colleagues have been examining how the fragile X protein (FMRP) acts as a “toggle switch.”

Gary Bassell, PhD

FMRP controls the activity of several genes by holding on to the RNAs those genes encode. When neurons get an electrochemical signal from the outside, FMRP releases the RNAs, allowing the RNAs to be made into protein, and facilitating changes in the neurons linked to learning and memory.

The Bassell lab’s new paper in Journal of Neuroscience reveals the role of another player in this process. The first author is postdoctoral fellow Vijay Nalavadi.

The researchers show that neurons modify FMRP with ubiquitin, the cellular equivalent of a tag for trash pickup, after receiving an external signal. In general, cells attach ubiquitin to proteins so that the proteins get eaten up by the proteasome, the cellular trash disposal bin. Here, neurons are temporarily getting rid of FMRP, prolonging the effects of the external signal.

Quite a lot, it turns out.Â At a time when large projects such as the Cancer Genome Atlas seek to define the changes in DNA that drive cancer formation, it is helpful to have the insight gained from other arenas, such as fruit flies, to make sense of the mountains of data.

Drosophila melanogaster has been an important model organism for genetics because the flies are easy to care for, reproduce rapidly, and have an easily manipulated genome. This NCI newsletter article describes how some investigators have used Drosophila to find genes involved in metastasis.

Emory cell biologist Ken Moberg says that he and postdoctoral fellow Melissa Gilbert crafted a Drosophila-based strategy to identify growth-regulating genes that previous researchers may have missed. Their approach allowed them to begin defining the function of a gene that is often mutated in lung cancer. The results are published online in Developmental Cell.

Part of the developing fly larva, stained with an antibody against Myopic. Groups of cells lacking Myopic, which lack green color, tend to divide more rapidly.

Moberg writes:

Many screens have been carried out in flies looking for single gene lesions that drive tissue overgrowth. But a fundamental lesson from years of cancer research is that many, and perhaps most, cancer-causing mutations also drive compensatory apoptosis, and blocking this apoptosis is absolutely required for cancer outgrowth.

We reasoned that this class of ‘conditional’ growth suppressor genes had been missed in prior screens, so we designed an approach to look for them. The basic pathways of apoptosis are fairly well conserved in flies, so itâ€™s fairly straight forward to do this.

Explanatory note: apoptosis is basically a form of cellular suicide, which can arise when signals within the cell clash; one set of proteins says â€œgrow, growâ€ and another says â€œbrake, brake,â€ with deadly results.

Gilbert identified the fruit fly gene Myopic as one of these conditional growth regulators. She used a system where mutations in Myopic drive some of the cells in the flyâ€™s developing eye to grow out more â€“ but only when apoptosis is disabled.

Gilbert showed that Myopic is part of a group of genes in flies, making up the Hippo pathway, which regulates how large a developing organ will become. This pathway was largely defined in flies, then tested in humans, Moberg says. The functions of the genes in this pathway have been maintained so faithfully that in some cases, the human versions can substitute for the fly versions.

Myopicâ€™s ortholog (ie different species, similar sequence and function) is the gene His-domain protein tyrosine phosphatase, or HD-PTP for short. This gene is located on part of the human genome that is deleted in more than 90 percent of both small cell and non-small cell lung cancers, and is also deleted in renal cancer cells.

How HD-PTP, when it is intact, controls the growth of cells in the human lung or kidney is not known. Gilbert and Mobergâ€™s findings suggest that HD-PTP may function through a mechanism that is similar to Myopicâ€™s functions in the fly.

Besides clarifying what Myopic does in the fly, their paper essentially creates a map for scientists studying HD-PTPâ€™s involvement in lung cancer, for example, to probe and validate.

An article in the April 2011 issue of Nature Medicine highlights the mechanistic overlap between autism and epilepsy.

By studying how rare genetic conditions known to coincide with both epilepsy and autismâ€”such as Rett syndrome, fragile X syndrome and tuberous sclerosisâ€”unfold at an early age, neuroscientists are finding that both disorders may alter some of the same neural receptors, signaling molecules and proteins involved in the development of brain cell synapses.

Gary Bassell, PhD

Emory cell biologist Gary Bassell and his colleagues have been taking exactly this approach. Recently they published a paper in Journal of Neuroscience, showing that the protein missing in fragile X syndrome, FMRP, regulates expression of an ion channel linked to epilepsy. This could provide a partial explanation for the link between fragile X syndrome and epilepsy.

The Nature Medicine article also mentions a drug strategy, targeting the mTOR pathway, which Bassell’s group has been exploring with fragile X syndrome.

Cilia are tiny hair-like structures on the outside of cells. Your memory of cilia may extend back to biology class, when you saw a picture of a paramecium or lung tissues, where cilia keep surfaces free of dirt and mucus.

Ciliated cells in the human oviduct

In the last few years, scientists have been learning more about cilia’s many roles in the body. Nearly all mammalian cells have cilia, and they are thought to act more like antennae, sending and receiving signals.Â Defects in cilia have been connected to lung, heart, kidney and eye diseases. Accordingly, Emory’s 15th BCMB training grant symposium focuses on cilia, beginning Thursday evening with a keynote talk by Susan Dutcher from Washington University, St. Louis and extending all day Friday.

At Emory, cell biologistÂ Winfield Sale’s laboratory uses the model system of the alga Chlamydomonas to study dynein, a molecular motor that drives the functions of cilia. In addition,Â geneticist Tamara Caspary’s laboratory is studying how defects in cilia can lead to altered embryonic development. Ping Chen’s group has been examining cilia in the context of inner ear development.

This week’s program is sponsored by Emory’s graduate program in Biochemistry, Cell and Developmental Biology, the Departments of Cell Biology, Biochemistry, Pharmacology, Biology, Microbiology and Immunology, Physics, the Graduate Division of Biological and Biomedical Sciences and the Woodruff Health Sciences Center.

In a paper recently published in Journal of Neuroscience, a team led by cell biologist Gary Bassell shows that PI3 kinase inhibitors could restore normal appearance and levels of protein production at the synapses of hippocampal neurons from fragile X model mice. The next steps, studies in animals, are underway.

â€œThis is an important first step toward having a new therapeutic strategy for fragile X syndrome that treats the underlying molecular defect, and it may be more broadly applicable to other forms of autism,â€ he says.

“By integrating the fields of life sciences with engineering,” McIntire explains, “we can better understand the mechanisms of disease and develop new ways to diagnose and treat medical problems. We are working collaboratively in the fields of biomedical nanotechnology, predictive health, regenerative medicine, and health care robotics, among others.

If the brain acts like a computer, which of the brain’s physical features store the information? Flashes of electricity may keep memories and sensations alive for the moment, but what plays the role that hard drives and CDs do for computers?

A simple answer could be: genes turning on and off, and eventually, neurons growing and changing their shapes. But it gets more complicated pretty quickly. Genes can be regulated at several levels:

at the level of transcription — whether messenger RNA gets made from a stretch of DNA in the cell’s nucleus

at the level of translation — whether the messenger RNA is allowed to make a protein

at the level of RNA localization — where the mRNAs travel within the cell

Each neuron has only two copies of a given gene but will have many dendrites that can have more or less RNA in them. That means the last two modes of regulation offer neurons much more capacity for storing information.

Gary Bassell, a cell biologist at Emory, and his colleagues have been exploring how RNA regulation works in neurons. They have developed special tools for mapping RNA, and especially, microRNA — a form of RNA that regulates other RNAs.

In the dendrites of neurons, FMRP seems to control where RNAs end up

Fragile X mental retardation protein (FMRP), linked to the most common inherited form of mental retardation, appears to orchestrate RNA traffic in neurons. Bassell andÂ pharmacologist Yue Feng recently received a grant from the National Institute of Child Health and Development to study FMRP’s regulation of RNA in greater detail. The grant was one of several at Emory funded through the American Recovery and Reinvestment Act’s support for the NIH.

In the video interview above, Bassell explains his work on microRNAs in neurons. Below is a microscope image, provided by Bassell, showing the pattern of FMRP’s localization in neurons.